Novel use of selective pde5 inhibitors

a pde5 inhibitor and selective technology, applied in the field of new selective pde5 inhibitors, can solve the problems of deteriorating gas exchange function with decrease in the oxygen content of the patient's blood, poor or absolutely no ventilation area, etc., and achieve the effect of improving the gas exchange function

Inactive Publication Date: 2005-05-19
GHOFRANI ARDESCHIR +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0015] It has now been found, surprisingly, that selective PDE5 inhibitors are suitable for the treatment of patients having the abovementioned mismatch. Administration of selective PDE5 inhibitors leads to dilatation of vessels in the pulmonary circulation and,

Problems solved by technology

In the healthy lung both at rest and during exercise there are always areas of good and poor or absolutely no ventilation existing simultaneously side by side (ventilation inhomogeneity).
When this adaptation mechanism is impaired (“mismatch”), there may, despite adequate ventilation and normal perfusion of the lungs, be a more or less pronounced collapse of the gas exchange function, which can be compensated only inadequately despite a further increase in ventilation or perfusion.
The consequence of this mismatch are hypoxaemia (deterioration in gas exchange with decrease in the oxygen content of the patient's blood), wasted perfusion (uneconomical perfusion of unventilated areas) and wasted ventilation (uneconomical ventilation of poorly perfused areas).
This leads to a limitation in the patient's performance due to a deficient oxygen supply to the muscles in combination with a “squandering” of cardiorespiratory reserves.
The cause is inadequate adaptation of the intrapulmonary perfusion conditions to the inhomogeneous pattern of the distribution of ventilation.
This effect is particularly evident during exercise and when the oxygen demand is increased and i

Method used

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Examples

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Effect test

example 1

Isolated Perfused Lung

[0089] The isolated, ventilated rabbit lung with bloodless perfusion is an established organ model. Removal of the lung from the integrated organ system makes It possible for the experimental situation to be free of humoral, central and metabolic influences from the body for investigating the complete, isolated, but intact organ. The ex vivo experimental mode used permits continuous recording of measurements of biophysical parameters such as the pulmonary arterial pressure, the ventilation pressure and the lung weight. Modification of the basic design additionally made alveolar deposition of substances possible through nebulization in the present study.

[0090] New Zealand White crossbred rabbits of both sexes weighing between 2.6 and 2.8 kg were used to carry out this series of experiments. A marginal ear vein was punctured for injection of the necessary substances. The animals were then sedated with a mixture of ketamine (Ketanest®) and xylazine (Rompun®) (2 / ...

example 2

Effect of Sildenafil on Bleomycin-induced Pulmonary Fibrosis

[0094] Healthy rabbits of both sexes were pretreated orally with a gyrase inhibitor (Baytril®) for one week. Ten animals pretreated in this way were not treated with bleomyin and served as control, and, on the day of exposure, the others were anaesthetized with a Ketanest® / Rompun® mixture, intubated intratracheally and ventilated mechanically. An ultrasonic nebulizer (MMAD 2.5 μm) was used to administer by inhalation exactly 1.8 U / kg of bodyweight of bleomycin under volume-controlled ventilation. After 4, 8, 16, 24, 32 and 64 days (in each case n≧5) post exposure, the animals were again anaesthetized, provided with an arterial access (right carotid artery) and underwent bodyweight-adapted ventilation via a tracheostomy in a volume-controlled method. The arterial pO2 and pCO2, and the static compliance of the lung were measured (by recording the intrathoracic pressure and with slow inflation / deflation manoeuvres). Subsequen...

example 3

Sildenafil in Patients with Chronic Thromboembolism

[0097] 7 patients with CTEPH underwent a Swan-Ganz catheter investigation with measurement of the ventilation / perfusion (V / Q) distribution (using the multiple inert gas elimination technique (MIGET)). After determination of the baseline parameters (haemodynamics and gas exchange), all the patients initially inhaled 20 ppm NO, followed by a second baseline period (10-15 min), and then PGI was infused (6 ng / kg bodyweight / min), again followed by a second baseline period (10-15 min) and then an oral dose of 50 mg of sildenafil was given (120-150 min follow-up). 3 of the 7 patients were controlled by continuous nasal oxygen therapy in order to reach an arterial oxygenation of >88%. The following parameters were measured under baseline conditions: mean pulmonary arterial pressure (mPAP) 52.1 + / −3.3 mmHg, cardiac index (CI) 2.2+ / −0.1 |* min−1*m−2, pulmonary vascular resistance index (PVRI) 1703.8+ / −129.5 dyn*s*cm−6*m2, arterial pO2 72.5+ / ...

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Abstract

The invention relates to the novel use of PDE5 inhibitors for the treatment of patients in which a mismatch is present.

Description

TECHNICAL FIELD [0001] The invention relates to novel use of selective PDE5 inhibitors in the treatment of pulmonary disorders. PRIOR ART [0002] In the healthy lung both at rest and during exercise there are always areas of good and poor or absolutely no ventilation existing simultaneously side by side (ventilation inhomogeneity). An as yet unknown mechanism ensures that there is ittle or no perfusion of the capillaries adjacent to alveoli with little or no ventilation. This occurs in order to minimize inefficient perfusion of areas of the lung which are not involved in gas exchange. [0003] Necessary for efficient gas exchange in the lung is a dynamic adaptation of the perfusion conditions to the continual changes in regional ventilation. This coupling is referred to as matching and is determined qualitatively and quantitatively as the V / Q ratio (ventilation / perfusion) by means of the multiple inert gas elimination technique (MIGET). [0004] During bodily exercise, the distribution o...

Claims

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Application Information

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IPC IPC(8): A61K31/00C07D487/04A61K31/496A61K31/4985A61K31/519A61K31/53A61K45/00A61P9/08A61P9/12A61P11/00A61P11/06A61P11/08
CPCA61K31/00A61K31/496A61K31/53A61K31/519A61K31/4985A61P11/00A61P11/06A61P11/08A61P9/08A61P9/12
Inventor GHOFRANI, ARDESCHIRGRIMMINGER, FRIEDRICH JOSEFSCHUDT, CHRISTIAN
Owner GHOFRANI ARDESCHIR
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